PROJECT SUMMARY Acute respiratory distress syndrome (ARDS) and sepsis claim the lives of hundreds of thousands of patients worldwide each year. Improved care has reduced mortality due to ARDS and sepsis, but up to 80% of ARDS/sepsis patients develop acute brain dysfunction in the form of delirium, a major complication associated with prolonged ICU and hospital stays and increased mortality. Even when delirium symptoms resolve, many patients never regain normal cognition, instead struggling with an acquired, dementia-like, long-term cognitive impairment. With a limited understanding of the pathophysiology of brain dysfunction due to ARDS and sepsis, there are currently no cognition-preserving therapies for ARDS/sepsis patients. Animal and human studies have shown that the inflammatory response of ARDS/sepsis imposes a stress on cells and tissues characterized by increased production of reactive oxygen species (ROS), decreased oxygen delivery, impaired oxygen consumption, metabolic reprogramming increasing lactate production, and dysregulation of cell proliferation/apoptosis. This stress response is mediated by mitochondria, which produce ROS, regulate oxygen and nutrient metabolism, and control initiation of apoptosis. Mitochondrial dysfunction has been implicated in sepsis-induced injury of lung (i.e., ARDS) as well as heart, muscle, and kidneys, but the most metabolically vulnerable organ?the brain?remains poorly studied in this context. We hypothesize that mitochondrial function and key variables that impact it, e.g., mitochondrial DNA (mtDNA) haplogroup, are major determinants of delirium and long-term cognitive impairment due to ARDS and sepsis. To test this central hypothesis, we will complete the following Aims: (1) Test the hypotheses that specific mtDNA haplogroups are independently associated with delirium and long-term cognitive impairment due to ARDS and sepsis; (2) test the hypotheses that alterations in mitochondrial oxidative metabolism, systemic oxidant injury, and mitochondrial injury are predicted by mtDNA haplogroup and are independently associated with delirium and long-term cognitive impairment due to ARDS and sepsis; and (3) test the hypotheses that alterations in multiple specific metabolic pathways affected by mitochondrial dysfunction in the brain are independently associated with delirium and long-term cognitive impairment due to ARDS and sepsis. We will complete Aim 1 using Vanderbilt?s BioVU DNA Databank and electronic medical record as well as data and DNA collected during the NIH-funded BRAIN-ICU study, Aim 2 using data and specimens collected in the BRAIN-ICU study, and Aim 3 using data and specimens collected from a prospective cohort of patients with ARDS and/or sepsis. By elucidating the pathophysiology of ARDS/sepsis-associated brain dysfunction, this work will in due course lead to strategies that preserve cognitive function for millions who will suffer from ARDS or sepsis in the future.